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众所周知，BRCA1是重要的肿瘤抑制基因，其突变携带者一生的乳腺癌发生风险高达40%～80%。BRCA1主要产物P220蛋白的功能丧失，通常引起基底样乳腺癌，其中大约80%与三阴性乳腺癌重合，但是具体过程尚不明确。 2019年6月27日，全球自然科学三大旗舰期刊之一、美国《细胞》正刊发表哈佛大学医学院、达纳法伯癌症研究所、布莱根和波士顿妇女医院、默克、麻省理工学院怀特海德生物医学研究所、罗格斯大学罗伯特伍德约翰逊医学院、荷兰皇家科学院乌得勒支大学医疗中心胡布雷希特研究所的研究报告，发现了BRCA1突变引起乳腺癌的关键过程。 该研究发现，BRCA1与乳腺上皮细胞的NUMB和HES1等多种蛋白质相互作用，形成参与DNA链间交联修复和乳腺上皮细胞分化调控的复合物。如果DNA链间交联损伤未被修复，可以引起人类乳腺基底样上皮细胞异常转分化为间质细胞以及原代小鼠乳腺管腔上皮细胞异常转分化为基底样或间质细胞。原代小鼠乳腺管腔上皮细胞的BRCA1、NUMB或HES1缺失或顺铂等化疗药物诱发链间交联损伤所致持续DNA损伤，可以引发管腔上皮细胞转分化为基底样或间质细胞。体内单细胞分析表明，小鼠BRCA1基底样乳腺癌发生期间，正常的乳腺管腔上皮细胞随着时间推移，通过转分化为基底样或间质细胞，逐渐演变为管腔祖细胞样肿瘤细胞。随着该恶性转化，DNA损伤不断增加。 因此，该研究结果表明，BRCA1突变所致乳腺正常上皮细胞DNA损伤如果未被充分修复，可以逐渐转分化为基底样或间质细胞，从而引发基底样乳腺癌，故为阻断BRCA1突变所致乳腺癌指明了道路。 Cell. 2019 Jun 27;178(1):135-151.e19. Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer. Hua Wang, Dongxi Xiang, Ben Liu, Aina He, Helena J. Randle, Kelvin Xi Zhang, Anushka Dongre, Norman Sachs, Allison P. Clark, Luwei Tao, Qing Chen, Vladimir V. Botchkarev Jr., Ying Xie, Ning Dai, Hans Clevers, Zhe Li, David M. Livingston. Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Merck & Co., Boston, MA, USA; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Hubrecht Institute, Uppsalalaan, Utrecht, the Netherlands; Robert Wood Johnson Medical School, Rutgers, New Brunswick, NJ, USA. HIGHLIGHTS
Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation. KEYWORDS: breast cancer; BRCA1; NUMB; HES1; CtIP; cisplatin; ICL repair; EMT; cell fate; transdifferentiation; mouse model; single-cell analysis DOI: 10.1016/j.cell.2019.06.002
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